Cancer management involves surgery, radiotherapy and chemotherapy, which may be used alone or in combination, either simultaneously or sequentially.
Chemotherapy employs antineoplastic agents which are drugs that prevent or inhibit the maturation and proliferation of neoplasms. Antineoplastic agents work by effectively targeting fast-dividing cells. As antineoplastic agents affect cell division, tumors with high growth fractions (such as acute myelogenous leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. Malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly.
However, the development of chemoresistance is a persistent problem during chemotherapy treatment. For instance, the conventional treatment of acute myeloid leukemia (AML) comprises the combined administration of cytarabine with an anthracycline, such as daunorubicin. 5-year overall survival rate is 40% in young adults and around 10% for elderly patients. Response rates dramatically vary with ageing, from 40% to 55% in patients older than 60 years and from 24% to 33% in patients older than 70 years. This is even worse for elderly with adverse cytogenetic profiles and death within 30 days following therapy ranges from 10% to 50% with increasing age and worsening. Furthermore, the restriction of the use of these molecules is due also to secondary effects, and in particular the emergence of chronic cardiac toxicity (linked to anthracyclines). The intensive chemotherapy-related toxic death rate is 10-20% in patients over 60 years.
With this risk-benefit profile of the conventional regimen, only 30% of elderly with newly diagnosed AML receive antineoplastic chemotherapy. Over the last decades, there was only modest improvement of outcomes for younger patients with AML, but none for adults older than 60 years (most of patients with AML). This data underline the need of new combination approaches both to reduce dosage regimens of antineoplastic agents to treat chemosensitive tumors and by-pass resistance of chemoresistant tumors to antineoplastic agent.
Two main issues have to be overcome in order to reach these goals: 1) chemoresistance; 2) intrinsic toxicity of antineoplastic drugs.
Various hypotheses have been proposed to account for the phenomenon of chemoresistance. The hypothesis include altered transport of the drug across the plasma membrane, genetic responses, enhanced DNA repair, alteration in target molecules, access to target cells, metabolic effects and growth factors. Recently, small pumps on the surface of cancer cells that actively move chemotherapy drugs from inside the cell to the outside have been identified. Research on p-glycoprotein and other such chemotherapy efflux pumps is currently ongoing. Medications inhibiting the function of p-glycoprotein have been explored to enhance the efficacy of chemotherapy. However, this approach failed during clinical evaluation. (Kolitz J E et al, Blood 2010; Burnett A K et al, Br J Hematol 2009).
There is an urgent need to develop new therapy regimens to overcome chemoresistance of tumors or to increase the sensibility of tumors to antineoplastic drugs.
The pharmaceutically active compound 5α-hydroxy-6β-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3β-ol is known under the name Dendrogenin A. Its structural formula I is the following one:

Dendrogenin A is disclosed in WO03/89449 and de Medina et al (J. Med. Chem., 2009 and Nature Commun. 2013) and has been shown to induce cell death of various tumor cell lines.
Dendrogenin A is the first endogenous steroidal alkaloid identified in mammals. It was established that Dendrogenin A is enzymatically formed in mammalian tissue extracts and is a selective inhibitor of cholesterol epoxide hydrolase (de Medina et al., Nature Communications, 2013). Dendrogenin A induces tumor cell differentiation and immune cell infiltration. The properties of Dendrogenin A and its decreased level in tumors suggest a physiological function in maintaining cell integrity and differentiation.
Surprisingly, the present inventors have found that Dendrogenin A is able to restore the sensibility of tumors which are chemoresistant to an antineoplastic agent or to increase the effects of antineoplastic agents to tumors, which allows in turn reducing the effective cytotoxic dose of antineoplastic agents against chemosensitive tumors.